An elevated rate of basal hepatic glucose output is a characteristic feature of patients with Type II diabetes and fasting hyperglycemia. The etiology and mechanism(s) underlying this abnormality remain to be delineated. The studies outlined in the current proposal are designed to test the hypothesis that the elevated rate of hepatic glucose productionis due to the elevated glucagon levels seen in these patients in conjunction with decreased insulin levels and decreased hepatic insulin sensitivity (abnormalities well-documented in this disorder). The specific aims of the proposed studies are: 1) to define the independent roles of glucagon, insulin and hyperglycemia in modulating hepatic glucose output in Type II diabetics; 2) to define the contributions of glycogenolysis, gluconeogenesis, and various gluconeogenic precursors to the maintenance of the elevated hepatic glucose production; 3) to characterize the hepatic handling of ingested glucose alone and as aprt of a mixed meal in Type II diabetic subjects and 4) to define the impact of various therapeutic modalities upon these aspects of hepatic metabolism in Type II diabetic sujects. To accomplish these goals, studies are planned in Type II diabetics using somotastatin to suppress endogenous insulin and glucagon secretion. In this setting, infusions of glucagon, insulin and glucose in various combinations and amounts will be used to define the effects of each of these factors upon the liver. Validated isotopic techniques will be used employing various isotopes of glucose and gluconeogenic substrates to address the other issues. Studies will be done before and after therapy with diet, oral hypoglycemic agents and insulin in order to delineate the impact of these therapies upon the various aspects of hepatic metabolism. The results of these studies should lead to an enhanced understanding of Type II diabetes and a more rational therapeutic approach.